Obesity is a disease that has increased at an alarming rate. Today, 64.5 percent of adult Americans (about 127 million) are categorized as being overweight (body mass index >25) or obese (body mass index >30). Obesity is strongly associated with type 2 diabetes, hypertension, coronary heart disease, respiratory conditions, increased incidence of certain forms of cancer, and many other diseases. Each year, obesity causes at least 300,000 excess deaths in the U.S. and healthcare costs of American adults with obesity amount to approximately $100 billion. Diet and exercise are stalwart anti-obesity therapies but success is variable. With the valvular heart disease associated with fenfluramine and phentermine in the late 1990's and subsequent withdrawal of fenfluramine and dexfenfluramine anti-obesity agents from the market, there has been a reduction in use of products that have similar pharmacological activities. Currently approved anti-obesity therapies (see Table 1) work by stimulating noradrenergic receptors, inhibiting serotonin and norepinephrine reuptake, or inhibiting absorption of fats via inhibition of Iipase but results are variable and there are some associated side effects. Major advances in understanding the homeostatic system and neural pathways that regulate body weight have led to potential therapeutic agents with novel activities, such as leptin, ghrelin antagonists, and ciliary neurotrophic factor (CNTF). We have discovered a natural occurring (in dogfish sharks), novel aminosterol, MS1-1436, that causes body weight reduction in genetically obese or diet-induced obese rodents when administered via various routes and in dogs. This compound, also re-established normoglycemia in diabetic obese animals and lowered serum cholesterol levels. Two steps are necessary to elevate this compound to clinical development and will be the aims of this grant: 1) the mechanism(s) of action(s) or neural pathways used by this compound need to be elucidated and 2) a minimal dose/frequency and formulation that allows subcutaneous implantable, intranasal or oral bio-availability needs to be developed.